8-103324893-G-A

Position:

• chr8-103324893-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003506.4(FZD6):​c.787G>A​(p.Ala263Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FZD6 NM_003506.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.43

Genes affected

FZD6 (HGNC:4044): (frizzled class receptor 6) This gene represents a member of the 'frizzled' gene family, which encode 7-transmembrane domain proteins that are receptors for Wnt signaling proteins. The protein encoded by this family member contains a signal peptide, a cysteine-rich domain in the N-terminal extracellular region, and seven transmembrane domains, but unlike other family members, this protein does not contain a C-terminal PDZ domain-binding motif. This protein functions as a negative regulator of the canonical Wnt/beta-catenin signaling cascade, thereby inhibiting the processes that trigger oncogenic transformation, cell proliferation, and inhibition of apoptosis. Alternative splicing results in multiple transcript variants, some of which do not encode a protein with a predicted signal peptide.[provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30230796).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FZD6	NM_003506.4	c.787G>A	p.Ala263Thr	missense_variant	4/7	ENST00000358755.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FZD6	ENST00000358755.5	c.787G>A	p.Ala263Thr	missense_variant	4/7	1	NM_003506.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 22, 2022

The c.787G>A (p.A263T) alteration is located in exon 4 (coding exon 3) of the FZD6 gene. This alteration results from a G to A substitution at nucleotide position 787, causing the alanine (A) at amino acid position 263 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.76	.;T;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.5	L;L;.
MutationTaster	Benign	0.85	D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.44	T;T;T
Polyphen		0.87	P;P;.
Vest4		0.39
MutPred		0.39		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;
MVP		0.92
MPC		0.70
ClinPred		0.82	D
GERP RS		5.7
Varity_R		0.11
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-104337121;